Taxanes are diterpenes produced by the plants of the genus Taxus, and are widely used as chemotherapy agents. Examples of taxanes include paclitaxel (Taxol®), docetaxel (Taxotere® or Docecad), cabazitaxel, larotaxel, ortataxel, tesetaxel and the like.
Among them, paclitaxel is one of the most effective antineoplastic agents that has been widely prescribed to treat a wide variety of tumors, including ovarian carcinoma, breast cancer, head and neck cancers, non-small lung cancer, prostatic cancer, and advanced forms of Kaposi's sarcoma. One of the major limitations associated with this potent drug is its low aqueous solubility due to its extremely hydrophobic nature.
The water solubility of paclitaxel is ˜10 μg/mL and the lack of functional groups in its chemical structure precluded any possible salt formation to improve its solubility. Therefore, various approaches to solubilize paclitaxel have been carried out for more than a decade and the most successful one is Taxol® (Bristol-Myers Squibb), the commercially available formulation for intravenous administration, which is 6 mg/mL of paclitaxel in a 50:50% v/v mixture of Cremophor EL® and dehydrated ethanol.
However, the clinical application of Taxol® encountered many problems, including serious or even fatal hypersensitivity episodes due to histamine induction by Cremophor EL® and possible precipitation after dilution and leaching of the diethylhexyl phthalate (DEHP) from polyvinylchloride (PVC) infusion sets, necessitating the use of plasticizer-free containers or bags and causing inconvenience to medical staff and pain to patients. Besides, to alleviate the severe side-effects of Taxol® formulation, patients are often required to receive premedication and/or prolonged infusion regimen (up to 24 hours) leading to either inconvenient long infusion time for patients or increased hospitalization cost of the patients for the entire 6 to 24-hour infusion duration. Moreover, such measures normally would not completely eliminate the side effects.
Accordingly, many formulation approaches such as to reduce the infusion time, to increase the stability of formulation, to prepare non-toxic formulations without cremophor or reduced cremophor amount, etc. have been made and disclosed in U.S. Pat. No. 6,569,459 (Method of administration of paclitaxel-plasma protein formulation), U.S. Pat. No. 5,681,846 (Extended stability formulations for paclitaxel), U.S. Pat. No. 6,919,370 (Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof), U.S. Pat. No. 6,107,333 (Parenteral paclitaxel in a stable non-toxic formulation), etc.
However, in general, an oral formulation is preferred because of the several advantages over other methods of administration, especially intravenous administration. In addition to the flexibility of treatment, oral formulations are inexpensive, convenient and have higher rate of compliance.
Accordingly, there exists a clear need for oral compositions of a taxane including paclitaxel that are easy to prepare and have enhanced solubility and bioavailability.